Numerous studies indicate blood pressure (BP) is increased in individuals whose mothers had preeclampsia (PE). Currently the only treatment option for PE involves early delivery. Yet, birth before 37 weeks resulting in preterm or low birth weight (LBW) is also associated with increased BP in the offspring. Thus, there is a critical need to develop therapeutic interventions for PE that not only improve maternal health but also mitigate fetal growth restriction and increased BP in the offspring. The well-characterized model of Reduced Uterine Perfusion Pressure (RUPP) in the pregnant rat mimics many facets of PE. The Alexander laboratory reports that BP is increased in male but not female LBW or intrauterine growth restricted (IUGR) offspring in early adulthood. The etiology of increased BP in male IUGR involves enhanced BP sensitivity to angiotensin II (ANG II) and increased renal oxidative stress; whereas, renal anti-oxidant enzyme activity elevated in female IUGR that are normotensive in young adulthood. Preliminary data indicate AT1-AA is elevated in male IUGR suggesting a potential mediator of enhanced ANG II sensitivity, but the etiology of increased renal oxidative stress is not yet clear. The role of mitochondrial stress in the kidney in models of developmental insult is also unknown but may involve microRNAs. Thus, this project will use a clinically relevant model of IUGR to test the novel hypothesis that maternal interventions improve placental perfusion and transfer of nutrients alleviating impaired fetal growth resulting in protection from CV disease in IUGR offspring. Furthermore, we will test the novel hypotheses that elevated AT1-AA and microRNA-mediated mitochondrial oxidative stress is sex-specific in the etiology of increased BP in IUGR offspring. Aim 1 will test the hypothesis that maternal therapeutic interventions improve uteroplacental perfusion and transfer of nutrients mitigating IUGR and the developmental origins of increased blood pressure in growth restricted offspring. Aim 2: will test the hypothesis that increased AT1-AA contributes to the sex-specific increase in blood pressure in male growth restricted offspring, and that maternal therapeutic interventions mitigate this increase in blood pressure in male IUGR by reducing AT1-AA activity and enhanced sensitivity to angiotensin II. Aim 3 will test the hypothesis that increased renal oxidative stress in male growth restricted offspring originates from mitochondrial dysfunction induced by sex-specific altered expression of redox-related microRNAs in young adulthood and that premature aging contributes to increased CV risk in female growth restricted offspring.